The present invention relates to novel benzotriazoles, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention are potent inhibitors of MAP kinases, preferably p38 kinase. They are useful in the treatment of inflammation, osteoarthritis, rheumatoid arthritis, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders.
Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e.g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phospholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. Cell, 80, 179-278 (1995)]. Protein kinases can be categorized into five classes with the two major classes being, tyrosine kinases and serine/threonine kinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine/threonine(s) residues [Hunter, T. Methods in Enzymology (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
For most biological responses, multiple intracellular kinases are involved and an individual kinase can be involved in more than one signaling pathway. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can affect transcriptional and translational events, respectively. The involvement of kinases in transcriptional control is presently much better understood than their effect on translation as illustrated by the studies on growth factor induced signal transduction involving MAP/ERK kinase [Marshall, C. J. Cell, 80, 179 (1995); Herskowitz, I. Cell 80, 187 (1995); Hunter, T. Cell, 80, 225 (1995); Seger, R., and Krebs, E. G. FASEB J., 726-735 (1995)].
While many signaling pathways are part of normal cell homeostasis, numerous cytokines (e.g., IL-1 and TNF) and certain other mediators of inflammation (e.g., COX-2, and iNOS) are produced only as a response to stress signals such as bacterial lipopolysaccharide (LPS). Early evidence suggesting that the signal transduction pathway leading to LPS-induced cytokine biosynthesis involved protein kinases came from studies of Weinstein [Weinstein, et al., J. Immunol 151, 3829(1993)] but the specific protein kinases involved were not identified. Working from a similar perspective, Han [Han, et al., Science 265, 808(1994)] identified murine p38 as a kinase which is tyrosine phosphorylated in response to LPS. Additional evidence of the involvement of the p38 kinase in LPS-stimulated signal transduction pathway leading to the initiation of proinflammatory cytokine biosynthesis was provided by the discovery of p38 kinase (CSBP 1 and 2) by Lee [Lee; et al, Nature, 372, 739(1994)] as the molecular target for a novel class of anti-inflammatory agents. Thus, compounds that inhibit p38 will inhibit IL-1 and TNF synthesis in human monocytes. Such results have been reported by [Lee, et al., Int. J. Immunopharmac. 10(7), 835(1988)] and [Lee; et al., Annals N.Y. Acad. Sci., 696, 149(1993)].
It is now accepted that CSBP/p38 is a one of several kinases involved in a stress-response signal transduction pathway which is parallel to and largely independent of the analogous mitogen-activated protein kinase (MAP) kinase cascade (FIG. 1). Stress signals, including LPS, pro-inflammatory cytokines, oxidants, UV light and osmotic stress, activate kinases upstream from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38 which in turn phosphorylate heat shock protein Hsp 27. It is now known that MAPKAP-2 is essential for LPS induced TNFxcex1 biosynthesis [Kotlyarov et al. Nature Cell Biol., 1, 94 (1999), see also Cohen, P. Trends Cell Biol. 353-361(1997)].
In addition to inhibiting IL-1 and TNF, CSBP/p38 kinase inhibitors also decrease the synthesis of a wide variety of pro-inflammatory proteins including, IL-6, IL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to suppress the TNF-induced expression of VCAM-1 on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the IL-1 stimulated synthesis of collagenase and stromelysin. These and additional data demonstrate that CSBP/p38 is involved not only cytokine synthesis, but also in cytokine signaling [CSBP/p38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361 (1997)].
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g, Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These disease states include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis and Reiter""s syndrome; gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic xcex2 cell disfunction, Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985).
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, or ARC (AIDS related complex), keloid information, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyrosis.
Interleukin-8 (IL-8) is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysaccharide (LPS). IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophils into the inflammatory site) would benefit by compounds, which are suppressive of IL-8 production.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte-derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
Inhibition of signal transduction via CSBP/p38, which in addition to IL-1, TNF and IL-8 described above is also required for the synthesis and/or action of several additional pro-inflammatory proteins (i.e., IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highly effective mechanism for regulating the excessive and destructive activation of the immune system. This expectation is supported by the potent and diverse anti-inflammatory activities described for CSBP/p38 kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera. 279 (3); 1453-1461. (1996); Griswold, et al., Pharmacol. Comm., 7, 323-229 (1996)].
There remains a need for treatment, in this field, for compounds, which are cytokine suppressive anti-inflammatory drugs, i.e., compounds that are capable of inhibiting the CSBP/p38/RK kinase.
CSBP/p38/RK kinase inhibitors are well known to those skilled in the art. International Patent Publication WO 00/40243, published Jul. 13, 2000, refers to pyridine substituted pyridine compounds and states that these compounds are p38 inhibitors. International Patent Publication WO 00/63204, published Oct. 26, 2000, refers to substituted azole compounds and states that these compounds are p38 inhibitors. International Patent Publication WO 00/31065, published Jun. 2, 2000, refers to certain heterocyclic compounds and states that these compounds are p38 inhibitors. International Patent Publication WO 00/06563, published Feb. 10, 2000, refers to substituted imidazole compounds and states that these compounds are p38 inhibitors. International Patent Publication WO 00/41698, published Jul. 20, 2000, refers to certain xcfx89-carboxy aryl substituted diphenyl urea compounds and states that these compounds are p38 inhibitors. U.S. Pat. No. 5,716,955 refers to certain substituted imidazole compounds and states that these compounds are p38 inhibitors. U.S. Pat. No. 5,716,972 refers to certain pyridinyl substituted imidazole compounds and states that these compounds are p38 inhibitors. U.S. Pat. No. 5,717,100 refers to certain pyridinyl substituted imidazole compounds and states that these compounds are p38 inhibitors. U.S. Pat. No. 5,756,499 refers to certain substituted imidazole compounds and states that these compounds are p38 inhibitors. U.S. Provisional Application Nos. 60/274,791 and 60/274,840, both filed Mar. 9, 2001, refer to benzimidazolone and triazolopyridine p38 inhibitors, respectively.
The present invention relates to a compound of the formula 
wherein Het is an optionally substituted 5-membered heteroaryl containing one or two heteroatoms selected from nitrogen, sulfur and oxygen wherein at least one of said heteroatoms atoms must be nitrogen;
R2 is selected from the group consisting of hydrogen, (C1-C6)alkyl or other suitable substituents;
R3 is selected from the group consisting of hydrogen, (C1-C6)alkyl or other suitable substituents; and
s is an integer from zero to five;
and pharmaceutically acceptable salts and prodrugs thereof.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula 1. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The compounds of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds, salts and prodrugs of the present invention can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the present invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds.
The present invention also includes atropisomers of the present invention. Atropisomers refer to compounds of formula I that can be separated into rotationally restricted isomers.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
A xe2x80x9csuitable substituentxe2x80x9d is intended to mean a chemically and pharmaceutically acceptable functional group i.e., a moiety that does not negate the inhibitory activity of the inventive compounds. Such suitable substituents may be routinely selected by those skilled in the art. Illustrative examples of suitable substituents include, but are not limited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxo groups, mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HOxe2x80x94(Cxe2x95x90O)xe2x80x94 groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups, alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, arylsulfonyl groups and the like. Those skilled in the art will appreciate that many substituents can be substituted by additional substituents.
More specifically, the present invention also relates to a compound of the formula 
wherein Het is an optionally substituted 5-membered heteroaryl which taken together with (R3xe2x80x94)s phenyl is selected from the group consisting of 
R2 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heteroaryl and (C1-C10)heterocyclic; wherein each of the aforesaid (C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heteroaryl and (C1-C10)heterocyclic substituents may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C3-C10)cycloalkyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, formyl, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (phenyl-)2Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (phenyl-)2Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, phenyl-SO2xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, and (phenyl-)2Nxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; wherein two adjacent R2 substituents on said (C3-C10)cycloalkyl, phenyl, (C1-C10)heteroaryl or (C1-C10)heterocyclic may be taken together with the carbon or heteroatom to which they are attached to form a five to six membered carbocyclic or heterocyclic ring; wherein each of said moieties containing a phenyl alternative may optionally be substituted by one or two radicals independently selected from the group consisting of (C1-C6)alkyl, halo, (C1-C6)alkoxy, (C1-C6)alkyl and perhalo(C1-C6)alkoxy;
each R3 is independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-S, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94; wherein two adjacent R3 substituents may optionally be taken together to form a three to six membered carbocyclic or heterocyclic ring;
s is an integer from zero to five;
R4 and R5 are each independently selected from the group consisting of hydrogen, halo and R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94;
n is an integer from zero to six;
each B is independently a bond, xe2x80x94(CHR10)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(SO2)xe2x80x94, xe2x80x94(Cxe2x95x90)xe2x80x94, xe2x80x94O(Cxe2x95x90)xe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94SO2xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90)xe2x80x94, xe2x80x94SO2xe2x80x94(NR10)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR10)xe2x80x94, xe2x80x94(O)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR10)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94;
R5 and R7 are each independently selected from the group consisting of hydrogen, R14xe2x80x94(CR15H)pxe2x80x94, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, (C1-C6)alkyl-(SO2)xe2x80x94, phenyl-(SO2)xe2x80x94, H2Nxe2x80x94(SO2)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(SO2)xe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94(SO2)xe2x80x94, phenyl-NHxe2x80x94(SO2)xe2x80x94, (phenyl-)2Nxe2x80x94(SO2)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (phenyl-)2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90)xe2x80x94, and (C3-C10)cycloalkyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90)xe2x80x94, wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R5 and R7 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90)xe2x80x94, phenyl-(Cxe2x95x90)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90)xe2x80x94, HOxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[(C1-C6)alkyl-N]xe2x80x94, (C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from halo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl and perfluoro(C1-C6)alkoxy;
p is an integer from one to six;
R9 is selected from the group consisting of hydrogen, xe2x80x94CF3, xe2x80x94Cxe2x95x90N, R13xe2x80x94(R12CH)mxe2x80x94, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94; wherein two adjacent moieties on said R9 phenyl, (C1-C10)heterocyclic or (C3-C10)cycloalkyl substituents may be taken together with the carbon or heteroatom to which they are attached to form a five to six membered heterocyclic or carbocyclic ring;
m is an integer from one to six;
R10 is hydrogen, (C1-C6)alkyl-SO2xe2x80x94 or (C1-C6)alkyl;
R11 is hydrogen or (C1-C6)alkyl;
each R12 is independently selected from the group consisting of hydrogen, amino, (C1-C6)alkoxy or (C1-C6)alkyl;
R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94;
R14 is selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, phenyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, phenyl-SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, phenyl-NHxe2x80x94SO2xe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94SO2xe2x80x94, (phenyl-)2Nxe2x80x94SO2xe2x80x94, formyl, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, R6xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R6xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, R6xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, R16-(C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, perfluoro(C1-C6)alkyl and perfluoro(C1-C6)alkoxy;
each R15 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94;
each R16 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C1-C10)heterocyclic, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; wherein said (C1-C10)heterocyclic may optionally be substituted by one to three substituents independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino and [(C1-C6)alkyl]2-amino;
or R4 and R6 or R4 and R7 or R5 and R6 may be taken together with the atoms to which they are attached to form an optionally substituted five to ten membered saturated, unsaturated or aromatic ring optionally containing two to three heteroatoms independently selected from NH, N, O, S, SO or SO2; wherein said ring may be optionally substituted by one to three substituents independently selected from the group consisting of oxo, halo, (C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, phenyl-Sxe2x80x94, phenyl-(Sxe2x95x90O)xe2x80x94, phenyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94SO2xe2x80x94, phenyl-NHxe2x80x94SO2xe2x80x94, (phenyl)2xe2x80x94Nxe2x80x94SO2xe2x80x94, phenyl-[N(C1-C6)alkyl]-SO2xe2x80x94, formyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[(C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-[(C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, formamidyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (phenyl)2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (phenyl)2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C10)heteroaryl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C1-C10)heteroaryl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C1-C10)heteroaryl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C1-C10)heterocyclic]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C1-C10)heterocyclic]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-HNxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C3-C10)cycloalkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, [(C3-C10)cycloalkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94;
or the pharmaceutically acceptable salts thereof.
As used herein, the term xe2x80x9calkyl,xe2x80x9d as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl); optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl. The phrase xe2x80x9ceach of said alkylxe2x80x9d as used herein refers to any of the preceding alkyl moieties within a group such alkoxy, alkenyl or alkylamino. Preferred alkyls include (C1-C4)alkyl, most preferably methyl and ethyl.
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d refers to a mono or bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl.
As used herein, the term xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo or iodo or fluoride, chloride, bromide or iodide.
As used herein, the term xe2x80x9chalo-substituted alkylxe2x80x9d refers to an alkyl radical as described above substituted with one or more halogens included, but not limited to, chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl.
As used herein, the term xe2x80x9calkenylxe2x80x9d means straight or branched chain unsaturated radicals of 2 to 6 carbon atoms, including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl.
As used herein, the term xe2x80x9c(C2-C6)alkynylxe2x80x9d is used herein to mean straight or branched hydrocarbon chain radicals having one triple bond including, but not limited to, ethynyl, propynyl, butynyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl.
As used herein, the term xe2x80x9ccarbonylxe2x80x9d or xe2x80x9c(Cxe2x95x90O)xe2x80x9d (as used in phrases such as alkylcarbonyl, alkyl-(Cxe2x95x90O)xe2x80x94 or alkoxycarbonyl) refers to the joinder of the  greater than Cxe2x95x90O moiety to a second moiety such as an alkyl or amino group (i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy(Cxe2x95x90O)xe2x80x94NHxe2x80x94) refers to an alkyl carbamate group. The carbonyl group is also equivalently defined herein as (Cxe2x95x90O). Alkylcarbonylamino refers to groups such as acetamide.
As used herein, the term xe2x80x9cphenyl-[(C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94,xe2x80x9d as used herein, refers to a disubstituted amide group of the formula 
As used herein, the term xe2x80x9carylxe2x80x9d means aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic heterocyclic group usually with one heteroatom selected from O, S and N in the ring. In addition to said heteroatom, the aromatic group may optionally have up to four N atoms in the ring. For example, heteroaryl group includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl. Particularly preferred heteroaryl groups include oxazolyl, imidazolyl, pyridyl, thienyl, furyl, thiazolyl and pyrazolyl (these heteroaryls are most preferred of the R4, R5, R6 and R7 heteroaryls).
The term xe2x80x9cheterocyclicxe2x80x9d as used herein refers to a cyclic group containing 1-9 carbon atoms and 1 to 4 hetero atoms selected from N, O, S or NRxe2x80x2. Examples of such rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Examples of said monocyclic saturated or partially saturated ring systems are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3xazolidin-3-yl, isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl, 1,2,5-oxathiazin-4-yl and the like; optionally substituted by 1 to 3 suitable substituents as defined above such as fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy or (C1-C6)alkyl. Preferred heterocyclics include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
Alternative, as used herein refers to a substituent, group or moiety which contains as any component of the substituent, group or moiety the designated functionality. Thus the phrase xe2x80x9ceach of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R5 and R7 alternativesxe2x80x9d refers to the R5 and R7 substituents containing a phenyl, heterocyclic, heteroaryl or cycloalkyl functionality. In the present example the identified phenyl, heterocyclic, heteroaryl or cycloalkyl R5 and R7 substituents are R4xe2x80x94(CR15H)pxe2x80x94, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, phenyl-(SO2)xe2x80x94, phenyl-NHxe2x80x94(SO2)xe2x80x94, (phenyl-)2Nxe2x80x94(SO2)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (phenyl-)2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, and (C3-C10)cycloalkyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94.
Embodiment as used herein refers to specific groupings of compounds or uses into discrete subgenera. Such subgenera may be cognizable according to one particular substituent such as a specific R2 group. Other subgenera are cognizable according to combinations of various substituents, such as all compounds wherein R2 is methyl and R4 is a group of the formula R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero. The phrase xe2x80x9cin combination with each of the aforementioned embodimentsxe2x80x9d refers to combinations of the identified embodiment with each embodiment previously identified in the specification. Thus an embodiment of compounds wherein R2 is methyl xe2x80x9cin combination with each of the aforementioned embodimentsxe2x80x9d refers to additional embodiments comprising combinations of the R2 methyl embodiment with each embodiment previously identified in the specification.
A preferred embodiment of the present invention is that group of compounds of formula I wherein R2 is (C1-C6)alkyl, more preferably (C1-C5)alkyl, more preferably (C1-C4)alkyl, more preferably methyl, ethyl, or isopropyl.
Another embodiment of the present invention is that group of compounds of formula I, wherein R2 is optionally substituted (C3-C6)cycloalkyl, more preferably optionally substituted cyclobutyl or cyclopentyl; more preferably optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, hydroxy, (C1-C6)alkoxy, amino, trifluoromethoxy, and (C1-C6)alkyl.
Another embodiment of the present invention is that group of compounds of formula I wherein R2 is optionally substituted phenyl; more preferably optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, hydroxy, (C1-C6)alkoxy, amino, trifluoromethoxy, and (C1-C6)alkyl.
Another embodiment of the present invention is that group of compounds of formula I wherein R2 is optionally substituted (C1-C10)heterocyclic, more preferably optionally substituted tetrahydrofuranyl, more preferably optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, hydroxy, (C1-C6)alkoxy, amino, trifluoromethoxy, and (C1-C6)alkyl.
Another embodiment of the present invention include that group of compounds of formula I wherein R2 is optionally substituted (C1-C10)heteroaryl, more preferably optionally substituted thiophenyl and pyridinyl, more preferably optionally substituted by 1 to 2 substituents independently selected from the group consisting of fluoro, chloro, trifluoromethyl, hydroxy, (C1-C6)alkoxy, amino, trifluoromethoxy, and (C1-C6)alkyl.
Another embodiment of the present invention is that group of compounds of formula I, wherein R2 is hydrogen.
An embodiment of the present invention includes compounds of formula I, referred to as the phenyl-pyrolyl-benzotriazoles, wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(a) in combination with each of the aforementioned embodiments of R2.
An embodiment of the present invention includes compounds of formula I, referred to as the phenyl-imidazolyl-benzotriazoles, wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(b) in combination with each of the aforementioned embodiments of R2.
Another embodiment of the present invention includes compounds of formula I, referred to as the phenyl-pyrazolyl-benzotriazoles, wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(c) in combination with each of the aforementioned embodiments of R
Another embodiment of the present invention includes compounds of formula I, referred to as the phenyl-oxazolyl-benzotriazoles, wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(d) in combination with each of the aforementioned embodiments of R2.
Another embodiment of the present invention includes compounds of formula I, referred to as the phenyl-isoxazolyl-benzotriazoles, wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(e) in combination with each of the aforementioned embodiments of R2.
Another embodiment of the present invention, referred to as the phenyl-pyrazolyl-benzotriazoles, are those group of compounds of formula I wherein the compound has the be formula 
Other embodiments of the present invention include those compounds of formula I(f) in combination with each of the aforementioned embodiments of R2.
Another embodiment of the present invention, referred to as the phenyl-thiazolyl-benzotriazoles, are those group of compounds of formula I wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(g) in combination with each of the aforementioned embodiments of R2.
Another embodiment of the present invention, referred to as the phenyl-isothiazolyl-benzotriazoles, are those group of compounds of formula I wherein the compound has the formula 
Other embodiments of the present invention include those compounds of formula I(h) in combination with each of the aforementioned embodiments of R2.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is hydrogen. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is hydrogen in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is an integer from one to six, more preferably one to five. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is one to six, preferably one to five, in combination with the aforementioned embodiments of R2.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is a bond and R9 is R13xe2x80x94(R12CH)mxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94, n is zero and R9 is R13xe2x80x94(R12CH)mxe2x80x94 in combination with the aforementioned embodiments of R2. More preferred embodiments of the invention of formula I (and I(c), I(e) and I(f)) are those compounds wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94, n is zero, R9 is R13xe2x80x94(R2CH)mxe2x80x94, m is one to six and R and R13 are each hydrogen.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is selected from the group consisting of hydrogen and R13xe2x80x94(R12CH)mxe2x80x94; more preferably wherein R9 is R13xe2x80x94(R2CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; R9 is hydrogen or R13xe2x80x94(R12CH)mxe2x80x94; more preferably wherein R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is as described above, in combination with the aforementioned embodiments of R2.
Another more preferred embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(R10xe2x80x94N)xe2x80x94; R9 is hydrogen or R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(R10xe2x80x94N)xe2x80x94; R9 is hydrogen or R13xe2x80x94(R 2CH)mxe2x80x94; m is 1 to xe2x88x926; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C5)alkyl, hydroxy, (C1-C6)alkoxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl, in combination with the aforementioned embodiments of R1 and R2. More preferred embodiments of the invention is that group of compounds of formula I (and I(c), I(e) and I(f)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94, n is zero, B is xe2x80x94(R10xe2x80x94N)xe2x80x94, R9 is R13xe2x80x94(R12CH)m, m is 1 to 6, and R10, R12 and R13 are each hydrogen.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is a bond, and R9 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is a bond, and R9 is as described above, in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR1)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is as described above, in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is as described above, in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is as described above, in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), (e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is R13xe2x80x94(R2CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 as described above, in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is R3xe2x80x94(R2CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R4 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to xe2x88x926; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is as described above, in combination with the aforementioned embodiments of R2.
Another embodiment of the present invention is that group of compounds of formula I (and I(c) and I(f)) wherein R7 is selected from the group consisting of hydrogen, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R7 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of said phenyl and heteroaryl moieties may optionally be substituted by one or two radicals independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino and [(C1-C6)alkyl]2-amino. Other embodiments of the present invention include those compounds of formula I (and I(c) and I(f)) wherein R7 is as defined above, in combination with each of the aforementioned I(c) and I(f) R4 embodiments and with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(c) and I(f)) wherein R7 is selected from the group consisting of R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R7 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C8)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino and [(C1-C6)alkyl]2-amino. Other embodiments of the present invention include those compounds of formula I (and I(c) and I(f)) wherein R7 is as defined above, in combination with each of the aforementioned I(c) and I(f) R4 embodiments and with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(c) and I(f)) wherein R7 is selected from the group consisting of hydrogen, and optionally substituted phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl. Other embodiments of the present invention include those compounds of formula I (and I(c) and I(f)) wherein R7 is as defined above, in combination with each of the aforementioned l(c) and I(f) R4 embodiments and with each of the aforementioned R2 embodiments. A more preferred embodiment of the present invention is that group of compounds of formula I(c) wherein R7 is hydrogen.
Another embodiment of the present invention is that group of compounds of formula I (and I(c) and I(f)) wherein R7 is R14xe2x80x94(CR15H)pxe2x80x94; p is one to six, preferably one to four; and R14 is selected from the group consisting of hydrogen, halo, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, formyl, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R6xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, R1xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R6xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[(C1-C6)alkyl-N]xe2x80x94, R16xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16-(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, R16xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino or [(C1-C6)alkyl]2-amino;
each R15 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C8)alkoxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C8)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; and
each R16 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(c) and I(f)) wherein R7 is as defined above, in combination with each of the aforementioned I(c) and I(f) R4 embodiments and with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(c) and I(f)) wherein R7 is R14xe2x80x94(CR15H)pxe2x80x94; p is one to four; R14 is selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[Nxe2x80x94((C1-C6)alkyl)]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, phenoxy, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino and R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R16-(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C-C6)alkyl)xe2x80x94N]xe2x80x94 and R16xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94;
each R15 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; wherein no more than two of said R15 groups may be other than hydrogen; and
each R16 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(c) and I(f)) wherein R7 is as defined above, in combination with each of the aforementioned I(c) and I(f) R4 embodiments and with each of the aforementioned R2 embodiments.
A more preferred embodiment of the present invention are those group of compounds of formula I(c) wherein R7 is R14xe2x80x94(CR15H)pxe2x80x94; p is one to four; R14 is selected from the group consisting of hydrogen, (C2-C4)alkenyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C3)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C3)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C2)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C3)alkoxy, amino, (C1-C4)alkylamino, [(C1-C4)alkyl]2-amino and (C1-C3)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; and each R15 is independently selected from the group consisting of hydrogen, (C1-C2)alkyl, hydroxy, and amino. More preferred compounds of formula I(c) are those compounds wherein the combined molecular weight of the R4 and R7 substituents is less than 200 AMU. More preferably, the combined molecular weight of the R4 and R7 substituents is less than 100 AMU.
Another embodiment of the present invention is that group of compounds of formula I (and I(b)) wherein R5 is hydrogen. Other embodiments of the present invention include those compounds of formula I (and I(b)) wherein R5 is hydrogen, in combination with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(b)) wherein R5 is (C1-C10)heterocyclic or (C1-C10)heteroaryl; wherein each of the aforesaid heterocyclic and heteroaryl substituents may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94 and [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(b)) wherein R5 is said optionally substituted (C1-C10)heterocyclic or (C1-C10)heteroaryl, in combination with each of the aforementioned R2 embodiments. More preferred heterocyclic groups are pyrrolidinyl, piperidinyl and azetidinyl.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(b)) wherein R5 is R14xe2x80x94(CHR15)pxe2x80x94, p is 1 to 6; and R14 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, phenyl-(Sxe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2, phenyl-SO2xe2x80x94, H2Nxe2x80x94SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, phenyl-NHxe2x80x94SO2xe2x80x94, [(C1-C6)alkyl-]2Nxe2x80x94SO2xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-[Nxe2x80x94(C1-C6)alkyl]-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16(xe2x80x94C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, R6xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R6xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R14 alternatives may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C3-C10)cycloalkyl, phenyl, benzyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, (C1-C6)alkyl-SO2xe2x80x94, formyl, xe2x80x94CN, R16xe2x80x94(C1-C,)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C3-C10)cycloalkyl-Oxe2x80x94, phenoxy, (C1-C10)heterocyclic-Oxe2x80x94, (C1-C10)heteroaryl-Oxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-clo)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, R16xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[(C1-C6)alkyl-N]xe2x80x94, R16xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94, (C3-C10)cycloalkyl-SO2NHxe2x80x94, phenyl-SO2NHxe2x80x94, (C1-C10)heterocyclic-SO2NHxe2x80x94 and (C1-C10)heteroaryl-SO2NHxe2x80x94; and wherein each of said phenyl and heteroaryl moiety alternatives may optionally be substituted by one or two radicals independently selected from halo, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6)alkylamino and [(C1-C6)alkyl]2-amino. Other embodiments of the present invention include those compounds of formula I (and I(b)) wherein R5 is said R14xe2x80x94(CHR15)pxe2x80x94, p is I to xe2x88x926; and R14 is as defined above, in combination with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(b)) wherein R5 is R14xe2x80x94(CHR15)pxe2x80x94, p is 1 to 6; and R14 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C10)cycloalkyl, phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, phenoxy, amino, R15xe2x80x94(C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; wherein each of the aforesaid phenyl, heterocyclic, heteroaryl or cycloalkyl R14 substituents may optionally be independently substituted by one to four moieties independently selected from the group consisting of halo, R16xe2x80x94(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, (C1-C6)alkyl-SO27, formyl, xe2x80x94CN, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, R16xe2x80x94(C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, R16xe2x80x94(C1-C6)alkoxy, perhalo(C1-C6)alkoxy, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, amino, R16xe2x80x94(C1-C6)alkylamino, [(Cxe2x80x94C6)alkyl]2-amino, formamidyl, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, R16xe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)-N]xe2x80x94 and R16xe2x80x94(C1-C6)alkyl-SO2NHxe2x80x94;
each R15 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; wherein no more than two of said R15 groups may be other than hydrogen; and
each R16 is independently selected from the group consisting of hydrogen, halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94.
Other embodiments of the present invention include that group of compounds of formula I (and I(b)) wherein R5 is said R14xe2x80x94(CHR15)pxe2x80x94, p is 1 to 6; and R14, R15 and R16 are as defined above, in combination with each of the aforementioned R2 embodiments.
A more preferred embodiment of the present invention are those group of compounds of formula I (and I(b)) wherein R5 is R14xe2x80x94(CHR15)pxe2x80x94, p is 1 to 6; and R14 is selected from the group consisting of hydrogen, (C2-C4)alkenyl, (C1-C10)heterocyclic, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C3)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C3)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, hydroxy, (C1-C3)alkoxy, amino, (C1-C3)alkylamino, and [(C1-C2)alkyl]2-amino; and each R15 is independently selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy, (C1-C3)alkoxy, perhalo(C1)alkoxy, amino, (C1-C2)alkylamino, [(C1-C2)alkyl]2-amino, formamidyl and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94; wherein no more than two of said R15 groups may be other than hydrogen.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is hydrogen. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is hydrogen, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is an integer from one to six, more preferably from one to five. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is an integer from one to six, more preferably from one to five, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is a bond and R9 is selected from the group consisting of hydrogen, xe2x80x94CF3, xe2x80x94Cxe2x89xa1N, (C1-C10)heteroaryl, (C1-C10)heterocyclic or (C3-C10)cycloalkyl; wherein each of the aforesaid (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl may optionally be substituted by one to three moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, perhalo(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero; B is a bond and R9 is as defined above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94SO2xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94,  greater than Cxe2x95x90O, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94(NR11)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94; and
R9 is selected from the group consisting of hydrogen, (C3-C10)cycloalkyl or phenyl; wherein the aforesaid phenyl and (C3-C10)cycloalkyl may optionally be substituted by one to three moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C8)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94SO2xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94,  greater than Cxe2x95x90O, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94(NR10)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94; and R9 is as defined above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is a bond; R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, phenyl-SO2xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl]-, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[Nxe2x80x94((C1-C6)alkyl)]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero; B is a bond; R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is as defined above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94,  greater than Cxe2x95x90O, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94; R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, phenyl-SO2xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl]-, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[Nxe2x80x94((C1-C6)alkyl)]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is zero; B is xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94SO2xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94,  greater than Cxe2x95x90O, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94(NR10)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94; and R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is as defined above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g))wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is as described above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heterocyclic, (C1-C10)heteroaryl and (C3-C10)cycloalkyl; wherein each of the aforesaid R9 phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl substituents may optionally be substituted by one to four moieties independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; and R9 is as described above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is a bond, and R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-SO2xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(c), I(e), I(f), and I(h)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six, more preferably one to five, more preferably one to three; B is xe2x80x94(Cxe2x95x90O)xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94SO2xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94; R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; each R12 is independently selected from the groups consisting of hydrogen or methyl; and R13 is as described above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
Another preferred embodiment of the present invention is that group of compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94; n is an integer from one to six; B is xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94,  greater than Cxe2x95x90O, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94; R9 is R13xe2x80x94(R12CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, phenyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, phenyl-SO2xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[N(C1-C6)alkyl]-, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[Nxe2x80x94((C1-C6)alkyl)]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(d), I(g)) wherein R6 is R9xe2x80x94Bxe2x80x94(CH2)nxe2x80x94 and n is 1 to 6; B is xe2x80x94(Cxe2x95x90O)xe2x80x94NR10xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94SO2xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94,  greater than Cxe2x95x90O, xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94(NR10)xe2x80x94, xe2x80x94(R10xe2x80x94N)xe2x80x94(Cxe2x95x90O)xe2x80x94(NR11)xe2x80x94; and R9 is R3xe2x80x94(R2CH)mxe2x80x94; m is 1 to 6; R10 is hydrogen or methyl; R12 is hydrogen or methyl; and R13 is as defined above, in combination with each of the aforementioned I(a) R4 embodiments, I(b) R5 embodiments or with each of the aforementioned R2 embodiments.
An embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and each R3 is independently selected from the group consisting of halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, perhalo(C1-C6)alkyl, phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic, (C3-C10)cycloalkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, xe2x80x94CN, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94 and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and each R3 is independently selected from the group consisting of halo, xe2x80x94CN, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and perhalo(C1-C6)alkyl. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and zero, one or two of R3 are independently selected from the group consisting of halo, (C1-C6)alkyl, perhalo(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, xe2x80x94CN, and H2N(Cxe2x95x90O)xe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and one of R3 is selected from the group consisting of optionally substituted phenyl, (C1-C10)heteroaryl, (C1-C10)heterocyclic and (C3-C10)cycloalkyl. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and one of R3 is selected from the group consisting of hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, phenoxy, (C1-C10)heteroaryl-Oxe2x80x94, (C1-C10)heterocyclic-Oxe2x80x94, (C3-C10)cycloalkyl-Oxe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-SO2xe2x80x94 and (C1-C6)alkyl-NHxe2x80x94SO2xe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and one of R3 is selected from the group consisting of amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, (C1-C6)alkyl-SO2xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94[((C1-C6)alkyl)xe2x80x94N]xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94 and phenyl-(Cxe2x95x90O)xe2x80x94[Nxe2x80x94(C1-C6)alkyl]-. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R3 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to four and one of R3 is selected from the group consisting of (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, phenyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C1-C10)heteroaryl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C10)heterocyclic-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C10)cycloalkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2N(Cxe2x95x90O)xe2x80x94 (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, phenyl-[((C1-C6)alkyl)xe2x80x94N]xe2x80x94(Cxe2x95x90O)xe2x80x94 and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Another embodiment of the present invention is that group of compounds of formula I wherein s is an integer from zero to three and each R3 is independently selected from the group consisting of halo, (C1-C6)alkyl, perhalo(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy, xe2x80x94NO2, amino, (C1-C6)alkylamino, [(C1-C6)alkyl]2-amino, xe2x80x94CN, and H2N(Cxe2x95x90O)xe2x80x94. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
Preferred compounds of the present invention is that group of compounds of formula I wherein s is an integer from zero to two and each R3 is independently selected from the group consisting of halo, (C1-C6)alkyl, perhalo(C1-C6)alkyl, (C1-C6)alkoxy, perhalo(C1-C6)alkoxy and xe2x80x94CN. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
More preferred compounds of the present invention is that group of compounds of formula I wherein s is an integer from zero to three and each R3 is independently selected from the group consisting of fluoro, chloro and methyl. Other embodiments of the present invention include those compounds of formula I (and I(a), I(b), I(c), I(d), I(e), I(f) and I(g)) wherein R3 is as defined above in combination with each of the aforementioned R6 embodiments, R7 embodiments, R4 embodiments, R5 embodiments or with each of the aforementioned R2 embodiments.
An embodiment of the (isoxazole-5-yl)-benzoimidazoles are those compounds wherein R4 is hydrogen. Another embodiment of the (isoxazole-5-yl)-benzoimidazoles are those compounds wherein R4 is other than hydrogen.
Examples of specific preferred compounds of the formula I are the following:
6-[5-(4-fluoro-3-methyl-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(4-fluoro-3-methyl-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
1-Isopropyl-6-(5-phenyl-3H-imidazol-4-yl)-1H-benzotriazole;
1-Isopropyl-6-(4-phenyl-oxazol-5-yl)-1H-benzotriazole;
6-[5-(4-fluoro-3-methyl-phenyl)-3H-imidazol-4-y]-1-methyl-1H-benzotriazole;
6-[5-(4-fluoro-phenyl)-2-pyridin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole; and
6-[5-(4-fluoro-phenyl)-2-pyrazin-2-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole.
Examples of other compounds of the formula I are the following:
6-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1-methyl-1H-benzotriazole;
1-methyl-6-(5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;
1-methyl-6-(5-phenyl-3H-imidazol-4-yl)-1H-benzotriazole;
1-Ethyl-6-(4-m-tolyl-oxazol-5-yl)-1H-benzotriazole;
1-Ethyl-6-(5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;
1-Ethyl-6-[4-(4-fluoro-phenyl)-oxazol-5-yl]-1H-benzotriazole;
1-Ethyl-6-[5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1H-benzotriazole;
6-[3-benzyl-5-(4-fluoro-3-methyl-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(4-fluoro-phenyl)-3S-pyrrolidin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole mono citrate salt;
6-[5-(4-fluoro-phenyl)-3R-pyrrolidin-3-yl-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
1-methyl-6-(2-pyrazin-2-yl-5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;
n-[5-(3-methyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazol-2-yl]-acetamide;
1-methyl-6-(2-pyridin-3-yl-5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;
1-isopropyl-6-(2-pyridin-3-yl-5-m-tolyl-3H-imidazol-4-yl)-1H-benzotriazole;
6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(3-Chloro-4-fluoro-phenyl)-thiazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[3-(3-Chloro-4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[3-(3-Chloro-4-fluoro-phenyl)-5-methyl-isothiazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[3-(3-Chloro-4-fluoro-phenyl)-5-methyl-1H-pyrazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[2-(3-Chloro-4-fluoro-phenyl)-1H-pyrrol-3-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(2-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(2-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(5-Chloro-2-fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(5-Chloro-2-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(3-Chloro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(3-Chloro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(3,4-Difluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(3,4-Difluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(3,4-Difluoro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;
6-[4-(3,4-Difluoro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;
6-[4-(3-Chloro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;
6-[5-(3-Chloro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;
6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;
6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;
6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-(2-chloro-phenyl)-1H-benzotriazole;
6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-(2-chloro-phenyl)-1H-benzotriazole;
6-[5-(4-Fluoro-phenyl)-3H-imidazol-4-yl]-1-phenyl-1H-benzotriazole;
6-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;
1-Phenyl-6-(4-phenyl-oxazol-5-yl)-1H-benzotriazole;
6-[4-(4-Fluoro-3-methyl-phenyl)-oxazol-5-yl]-1-phenyl-1H-benzotriazole;
6-[4-(3-Chloro-4-fluoro-phenyl)-oxazol-5-yl]-1-isobutyl-1H-benzotriazole;
6-[5-(3-Chloro-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isobutyl-1H-benzotriazole;
6-[5-(2,5-Difluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(2,5-Difluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(3-Bromo-4-fluoro-phenyl)-oxazol-5-y]-1-isopropyl-1H-benzotriazole;
6-[5-(3-Bromo-4-fluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[5-(2,4-Difluoro-phenyl)-3H-imidazol-4-yl]-1-isopropyl-1H-benzotriazole;
6-[4-(2,4-Difluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole;
4-Phenyl-5-(3-phenyl-3H-benzotriazol-5-yl)-1l H-imidazole-2-carboxylic acid amide;
4-(4-Fluoro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylic acid amide;
4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylic acid amide;
4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylic acid;
1-[4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazol-2-yl]-ethanone;
1-[5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazol-2-yl]-ethanone;
5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazole-2-carboxylic acid;
5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazole-2-carboxylic acid amide;
5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazole-2-carboxylic acid methyl ester;
[5-(3-Phenyl-3H-benzotriazol-5-yl)-4-m-tolyl-1H-imidazol-2-yl]-urea;
[4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazol-2-yl]-urea;
4-(3-Chloro-phenyl)-5-(3-phenyl-3H-benzotriazol-5-yl)-1H-imidazole-2-carboxylic acid methyl ester; and
5-[3-(2-Chloro-phenyl)-3H-benzotriazol-5-yl]-4-m-tolyl-1 H-imidazole-2-carboxylic acid amide.
The present invention also includes isotopically-labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
The compounds of Formula I or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal""s cells, such as but not limited to monocytes and/or macrophages.
Compounds of Formula (I) are capable of inhibiting proinflammatory cytokines, such as IL-1, IL-6, IL-8, and TNF and are therefore of use in therapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
Accordingly, the present invention provides a method of treating a cytokine mediated disease, which comprises administering an effective cytokine-interfering amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Certain compounds of Formula (I) are capable of inhibiting inducible pro-inflammatory proteins, such as COX-2, also referred to by many other names such as prostaglandin endoperoxide synthase-2 (PGHS-2) and are therefore of use in therapy. These proinflammatory lipid mediators of the cyclooxygenase (COX) pathway are produced by the inducible COX-2 enzyme. Regulation, therefore of COX-2 which is responsible for these products derived from arachidonic acid, such as prostaglandins, affect a wide variety of cells and tissues. Expression of COX-1 is not effected by compounds of Formula (I). This selective inhibition of COX-2 is accepted as alleviating or sparing ulcerogenic liability associated with inhibition of COX-1 thereby inhibiting prostaglandins essential for cytoprotective effects. Thus inhibition of these pro-inflammatory mediators is of benefit in controlling, reducing and alleviating many of these disease states. Most notably these inflammatory mediators, in particular prostaglandins, have been implicated in pain, such as in the sensitization of pain receptors, or edema. This aspect of pain management, therefore, includes treatment of neuromuscular pain, headache, cancer pain, and arthritis pain. Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are of use in therapy in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.
Accordingly, the present invention provides a method of inhibiting the synthesis of COX-2, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The present invention also provides for a method of treatment in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.
In particular, compounds of Formula (I) or a pharmaceutically acceptable salt thereof are of use in the therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated IL-1, IL-8 or TNF production by such mammal""s cells, such as, but not limited to, monocytes and/or macrophages.
Accordingly, in another aspect, this invention relates to a method of inhibiting the production of IL-1 in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These disease states include rheumatoid arthritis, osteoarthritis, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, stroke, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, Reiter""s syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-1 activity to diabetes, pancreatic p cells disease, and Alzheimer""s disease.
Use of a p38 inhibitor for the treatment of p38 mediated disease states, can include, but is not limited to neurodegenerative diseases, such as Alzheimer""s disease, Parkinson""s disease and multiple sclerosis, etc. In a further aspect, this invention relates to a method of inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, cerebral malaria, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, such as osteoporosis, cardiac, brain and renal reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, (including HIV-induced forms), cerebral malaria, meningitis, ischemic and hemorrhagic stroke, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, or ARC (AIDS related complex), keloid formation, scar tissue formation, inflammatory bowel disease, Crohn""s disease, ulcerative colitis and pyrosis.
Compounds of Formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo. The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibiting-compounds of Formula (I). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex. Accordingly, in a further aspect, this invention relates to a method of treating a mammal afflicted with a human immunodeficiency virus (HIV) which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
The compounds of Formula (I) may also be used topically in the treatment of topical disease states mediated by or exacerbated by excessive cytokine production, such as by IL-1 or TNF respectively, such as inflamed joints, eczema, contact dermatitis psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyrosis, pain and other conditions associated with inflammation. Periodontal disease has also been implemented in cytokine production, both topically and systemically. Hence, the use of compounds of Formula (I) to control the inflammation associated with cytokine production in such peroral diseases such as gingivitis and periodontitis is another aspect of the present invention.
Compounds of Formula (I) have also been shown to inhibit the production of IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, this invention relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering, to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. These diseases are characterized by massive neutrophil infiltration such as, psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with increased IL-8 production, which is responsible for the chemotaxis of neutrophils into the inflammatory site. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the unique property of promoting neutrophil chemotaxis and activation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neutrophil infiltration.
The compounds of Formula (I) are administered in an amount sufficient to inhibit a cytokine, in particular IL-1, IL-6, IL-8 or TNF, production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state. Abnormal levels of IL-1, IL-6, IL-8 or TNF, for instance in the context of the present invention, constitute: (i) levels of free (not cell bound) IL-1, IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1, IL-6, IL-8 or TNF, respectively, is produced.
The discovery that the compounds of Formula (I) are inhibitors of cytokines, specifically IL-1. IL-6, IL-8 and TNF is based upon the effects of the compounds of Formula (I) on the production of the IL-1, IL-8 and TNF in in vitro assays which are described herein or are well known to those skilled in the art.
As used herein, the term xe2x80x9cinhibiting the production of IL-1 (IL-6, IL-8 or TNF)xe2x80x9d refers to:
a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages;
b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels;
c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event to normal or sub-normal levels; or
d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels.
As used herein, the term xe2x80x9cTNF mediated disease or disease statexe2x80x9d refers to any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF.
As used herein, the term xe2x80x9ccytokinexe2x80x9d refers to any secreted polypeptide that affects the functions of cells and is a molecule, which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them. For instance, a monokine is referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-xcex1) and Tumor Necrosis Factor beta (TNF-xcex2).
As used herein, the term xe2x80x9ccytokine interferingxe2x80x9d or xe2x80x9ccytokine suppressive amountxe2x80x9d refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
As used herein, the cytokine referred to in the phrase xe2x80x9cinhibition of a cytokine for use in the treatment of a HIV-infected humanxe2x80x9d is a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
As TNF-xcex2 (also known as lymphotoxin) has close structural homology with TNF-xcex1 (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-xcex1 and TNF-xcex2 are inhibited by the compounds of the present invention and thus are herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise.
A relatively new member of the MAP kinase family, alternatively termed CSBP, p38 or RK, has been identified by several laboratories [See Lee et al., Nature, Vol. 300, n(72), 739-746 (1994)]. Activation of this protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-1 and tumor necrosis factor. The cytokine biosynthesis inhibitors, of the, present invention, compounds of Formula (i) have been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity, These inhibitors are of aid in determining the signaling pathways involvement in inflammatory responses. In particular, a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages. In addition to those diseases already noted herein, treatment of stroke, neurotrauma/CNS head injury, cardiac, brain and renal reperfusion injury, thrombosis, glomerulonephritis, diabetes and pancreatic p cells, multiple sclerosis, muscle degeneration, eczema, psoriasis, sunburn, and conjunctivitis are also included.
The cytokine inhibitors were subsequently tested in a number of animal models for anti-inflammatory activity. Model systems were chosen that were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of cytokine suppressive agents. The inhibitors exhibited significant activity in many such in vivo studies. Most notable are its effectiveness in the collagen-induced arthritis model and inhibition of TNF production in the endotoxic shock model. In the latter study, the reduction in plasma level of TNF correlated with survival and protection from endotoxic shock related mortality. Also of great importance are the compound""s effectiveness in inhibiting bone resorption in a rat fetal long bone organ culture system. Griswold et al., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ. Shock 27, 51-61, Votta et al., (1994) in vitro. Bone 15, 533-538; Lee et al., (1993.). B Ann. N.Y. Acad. Sci. 696, 149-170.
It is also recognized that both IL-6 and IL-8 are produced during rhinovirus (HRV) infections and contribute to the pathogenesis of common cold and exacerbation of asthma associated with HRV infection (Turner et al., (1998), Clin. Infec. Dis., Vol. 26, p. 840; Teren et al. (1997), Am. J. Respir. Crit. Care Med., Vol. 155, p. 1362; Grunberg et al. (1997), Am. J. Respir. Crit. Care Med., Vol. 156, p. 609 and Zhu et al., J. Clin. Invest. (1996), Vol. 97, p 421). It has also been demonstrated in vitro that infection of pulmonary epithelial cells with HRV results in production of IL-6 and IL-8 (Subauste et al., J. Clin. Invest. (1995), Vol. 96, p. 549). Epithelial cells represent the primary site of infection of HRV. Therefore, another aspect of the present invention is a method of treatment to reduce inflammation associated with a rhinovirus infection, not necessarily a direct effect of the virus itself.
Another aspect of the present invention involves the novel use of these p38/cytokine inhibitors for the treatment of chronic inflammatory or proliferative or angiogenic diseases, which are caused by excessive, or inappropriate angiogenesis.
Chronic diseases, which have an inappropriate angiogenic component, are various ocular neovascularizations, such as diabetic retinopathy and macular degeneration. Other chronic diseases, which have an excessive or increased proliferation of vasculature, are tumor growth and metastasis, atherosclerosis and certain arthritic conditions. Therefore, cytokine inhibitors will be of utility in the blocking of the angiogenic component of these disease states.
The term xe2x80x9cexcessive or increased proliferation of vasculature inappropriate angiogenesisxe2x80x9d as used herein includes, but is not limited to, diseases which are characterized by hemangiomas and ocular diseases.
The term xe2x80x9cinappropriate angiogenesisxe2x80x9d as used herein includes, but is not limited to, diseases which are characterized by vesicle proliferation with accompanying tissue proliferation, such as occurs in cancer, metastasis, arthritis and atherosclerosis.
This invention also encompasses methods of treating or preventing disorders that can be treated or prevented by the inhibition of ERKIMAP in a mammal, preferably a human, comprising administering to said mammal an effective amount of a compound of the formula 1.
Accordingly, the present invention provides a method of treating a p38 kinase mediated disease in a mammal in need thereof, preferably a human, which comprises administering to said mammal, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Preferred p38 mediated diseases for treatment include, but are not limited to psoriatic arthritis, Reiter""s syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer""s disease, stroke, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, cerebral malaria, meningitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcostosis, bone resorption disease, osteoporosis, restenosis, cardiac reperfusion injury, brain and renal reperfusion injury, chronic renal failure, thrombosis, glomerulonephritis, diabetes, diabetic retinopathy, macular degeneration, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, neurodegenerative disease, multiple sclerosis, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic disease, rhinovirus infection, peroral disease, such as gingivitis and periodontitis, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
This invention also encompasses pharmaceutical compositions for the treatment of a condition selected from the group consisting of arthritis, psoriatic arthritis, Reiter""s syndrome, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer""s disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerulonephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermatitis, psoriasis, sunburn, or conjunctivitis shock in a mammal, including a human, comprising an amount of a compound of formula I effective in such treatment and a pharmaceutically acceptable carrier.
This invention also encompasses pharmaceutical compositions for the treatment of a condition which can be treated by the inhibition of ERK/MAP kinase in a mammal, including a human, comprising an amount of a compound of formula I effective in such treatment and a pharmaceutically acceptable carrier.
This invention also encompasses pharmaceutical compositions for the treatment of a condition which can be treated by the inhibition of p38 kinase in a mammal, including a human, comprising an amount of a compound of formula I effective in such treatment and a pharmaceutically acceptable carrier.
This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula 1. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula 1. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
The present invention also encompasses sustained release compositions.
The present invention also relates to processes of preparing the compounds of formula I and intermediates used in such processes.
One of ordinary skill in the art will appreciate that the compounds of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the compounds of the invention may be combined with agents such as TNF-xcex1 inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (such as Enbrel(copyright)), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib) low dose methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold.
The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID""s) such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.
The compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, farnesyl transferase inhibitors, VegF inhibitors, and antimetabolites such as methotrexate.
The compounds of the invention may also be used in combination with antiviral agents such as Viracept, AZT, aciclovir and famciclovir, and antisepsis compounds such as Zovant, tifacogin, NOX-100 and GR270773.
The compounds of the present invention may also be used in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet aggregation inhibitors.
The compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti-Alzheimer""s drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
The compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin.